Lynne Howell

Our research activities are focused on understanding at the molecular and cellular level biological processes involved in microbial pathogenesis. The insights we gain from our fundamental research are used to develop novel strategies and treatments for bacterial and fungal biofilm related infections.

Dr. Howell’s research has led to the identification of several glycosyl hydrolases that are capable of both preventing biofilm formation and degrading preformed biofilms. These enzymes are being developed as combination therapies for the treatment of a range of bacterial and fungal infections, and as disinfectants and coatings for cleaning and protecting surfaces 

Microbial Biofilm Formation: From Molecular Mechanisms to Therapeutics

Molecular Mechanisms

A microbial biofilm is a surface attached community of microbial cells encased in a self-produced polymeric matrix. Biofilms grow on any moist biotic or abiotic surface, and provide a number of environmental advantages such as protecting microbes from the host immune response, and conferring tolerance to antibiotics and detergents. Established biofilms are extremely difficult to eradiate and cost the health care systems in the US and Canada upwards of $25 billion annually to treat. They are responsible for greater than 65-80% of all chronic bacterial infections.

Using a multidisciplinary approach, which combines in vivo microbiological studies with structural biology, biophysical and biochemical techniques, we want to understand at the molecular level how two critical fundamental processes occur:

1.  How are exopolysaccharides – a major component of the biofilm matrix – synthesized, chemically modified, and exported from the cell?
2. What is required for the assembly and function of type IV pili – key virulence factors used by Pseudomonas aeruginosa to establish infection and for biofilm formation?

Therapeutics

Our research on the biosynthetic machinery of various exopolysaccharides has led to the identification of several glycoside hydrolases that are capable of both preventing biofilm formation and degrading preformed biofilms. These enzymes are effective at low nano-molar concentration and are being developed as combination therapies for the treatment of a range of bacterial and fungal infections, and as disinfectants and coatings for cleaning and protecting surfaces.

Exopolysaccharide polymerization, modification and export.

Exopolysaccharides are a major component of many microbial biofilms. These long sugar polymers are often found both associated with the bacterial or fungal cell surface and in a secreted form. Exopolysaccharide biosynthesis is a multistep process that requires the polymerization of nucleotide-sugar precursors, and transport across either the cytoplasmic or plasma membrane. In the case of gram-negative bacteria the polymer also needs to transverse the periplasm and be exported from the cell. The properties of the polymer are frequently modulated by chemically modification, which can occur either in the periplasm or extracellular space.

Ongoing projects seek to determine the molecular mechanisms involved in the biosynthesis of:

• alginate;
• Pel polysaccharide;
• Psl polysaccharide;
• poly β-1,6-N-acetyl-D-glucosamine (PNAG); and
• galactosaminogalactan (GAG).

Assembly of Pseudomonas aeruginosa Type IV pili

Type IV pili (T4P) are strong flexible filaments that mediate attachment to both living and artificial surfaces. They are also involved in bacteriophage adsorption, DNA uptake, biofilm initiation and development, and “twitching motility”, a unique form of surface-associated movement whereby the bacteria pull themselves rapidly towards or along a surface by retracting their T4P. Bacteria lacking T4P cannot adhere to surfaces and are therefore avirulent.

Regulation and assembly of the T4P is a complex process involving over 50 proteins. We are interested in understanding how a subset of the proteins in this molecular machine interact with each other to assembly, extend and retract the pilus.

Courses Taught

BCH425H1 Structural Biology: Principles and Practise 
BCH473Y Advanced Research Project in Biochemistry

Awards

Fellow of the American Crystallographic Association
2013-2020 — Canada Research Chair in Structural Biology Research Award Canadian Government
2006-2013 — Canada Research Chair in Structural Biology Research Award Canadian Government
2001-2006 — Investigator Research Award Canadian Institutes of Health Research
1983-1986 — Studentship Research Award Science and Engineering Research Council of Great Britain